Cushing Syndrome in a Pediatric Patient With a KCNJ5 Variant and Successful Treatment With Low-dose Ketoconazole

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2021 Feb 25

PMID 33630995

Citations 3

Authors

Christina Tatsi

Andrea G Maria

Cole Malloy

Lin Lin

Edra London

Nick Settas

Chelsi Flippo

Meg Keil

Fady Hannah-Shmouni

Dax A Hoffman

Constantine A Stratakis

Affiliations

Soon will be listed here.

Abstract

Context: Pathogenic variants in KCNJ5, encoding the GIRK4 (Kir3.4) potassium channel, have been implicated in the pathogenesis of familial hyperaldosteronism type-III (FH-III) and sporadic primary aldosteronism (PA). In addition to aldosterone, glucocorticoids are often found elevated in PA in association with KCNJ5 pathogenic variants, albeit at subclinical levels. However, to date no GIRK4 defects have been linked to Cushing syndrome (CS).

Patient: We present the case of a 10-year-old child who presented with CS at an early age due to bilateral adrenocortical hyperplasia (BAH). The patient was placed on low-dose ketoconazole (KZL), which controlled hypercortisolemia and CS-related signs. Discontinuation of KZL for even 6 weeks led to recurrent CS.

Results: Screening for known genes causing cortisol-producing BAHs (PRKAR1A, PRKACA, PRKACB, PDE11A, PDE8B, ARMC5) failed to identify any gene defects. Whole-exome sequencing showed a novel KCNJ5 pathogenic variant (c.506T>C, p.L169S) inherited from her father. In vitro studies showed that the p.L169S variant affects conductance of the Kir3.4 channel without affecting its expression or membrane localization. Although there were no effects on steroidogenesis in vitro, there were modest changes in protein kinase A activity. In silico analysis of the mutant channel proposed mechanisms for the altered conductance.

Conclusion: We present a pediatric patient with CS due to BAH and a germline defect in KCNJ5. Molecular investigations of this KCNJ5 variant failed to show a definite cause of her CS. However, this KCNJ5 variant differed in its function from KCNJ5 defects leading to PA. We speculate that GIRK4 (Kir3.4) may play a role in early human adrenocortical development and zonation and participate in the pathogenesis of pediatric BAH.

Citing Articles

Adrenal Cushing's syndrome in children.

Guarnotta V, Emanuele F, Salzillo R, Giordano C Front Endocrinol (Lausanne). 2024; 14:1329082.

PMID: 38192416 PMC: 10773667. DOI: 10.3389/fendo.2023.1329082.

O tempora, o mores: The Age We Live In, Machine Learning, Hypertension, and Primary Aldosteronism.

Stratakis C JACC Asia. 2023; 3(4):676-677.

PMID: 37614549 PMC: 10442877. DOI: 10.1016/j.jacasi.2023.06.005.

Disorders of the adrenal cortex: Genetic and molecular aspects.

Pitsava G, Maria A, Faucz F Front Endocrinol (Lausanne). 2022; 13:931389.

PMID: 36105398 PMC: 9465606. DOI: 10.3389/fendo.2022.931389.

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